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Flashcards in 20 Protein Synthesis Inhibitors Cupo Deck (33):
1

What is some background information of Quinupristin/Dalfopristin?

Synercid. Alternative to Vancomycin given increased VREF rates. Member of Streptogramin class. 30:70 mixture of Quinupristin:Dalfopristin. (Quin = Streptogramin B, Dalfo = Streptogramin A)

2

What is the MOA of Quinupristin/Dalfopristin?

Sequential binding to separate sites on 50S ribosomal subunit, thus inhibiting protein synthesis. Dalfopristin, alters the ribosomal conformation such that the affinity for quinupristin is increased. A stable ternary complex of quinupristin-ribosome-dalfoprisin interrupts protein synthesis and causes cell death

3

What is the spectrum of activity for Quinupristin/Dalfopristin?

Predominantly Gram (+): S. aureus (MSSA, MRSA), S. epidermidis (MSSE, MRSE), E. faecium (includes vanc-R strains; not E. faecalis), S. pneumoniae (includes Pen-R strains), S. agalactiae, S. pyogenes, Viridans streptococci. Others (in vitro - clinical experience lacking): M. catarrhalis, Neisseria, Clostridium, Peptostreptococcus

4

What is the administration of Quinupristin/Dalfopristin?

IV only. Not FDA approved for < 16 years

5

What is the PK of Quinupristin/Dalfopristin?

T1/2: 1.3-1.5hrs (despite this, Q8h-Q12h dosing based on t1/2 of active metabolites). < 20% eliminated in urine, 75% in feces

6

What is the PD of Quinupristin/Dalfopristin?

Q + D = synergistic combination. Bactericidal except against E. faecium ("statis"). PAE: 6 hours (against S. aureus)

7

What is resistance like against Quinupristin/Dalfopristin?

"erm" gene (streptogramin B). Acetylation-induced drug inactivation, efflux pumps (streptogramin A)

8

What are the common ADRs associated with Quinupristin/Dalfopristin?

N/V/D (high). Athralgias, myalgias (may be up to 40% in debilitated pts w/ comorbidities, may require narcotic analgesics for pain control). Hyperbilirubinemia (reversible LFT increase). Infusion-site inflammation, pain, edema. Rash, thrombophlebitis

9

What is Quinupristin/Dalfopristin's place in therapy?

VRE. faecium bacteremia (usually Q8h, if hepatic insufficiency change to Q12h). MRSA bacteremia (alternative to vanco (esp. if intolerant to linezolid d/t bone marrow suppression), appears to also be synergistic with vanco)

10

What is Linezolid (Zyvox)?

Oxazolidinone class of antimicrobials ("novel mechanism"). Convenience of IV, PO dosage forms. Predominant Gram (+) activity

11

What is the MOA of Linezolid (Zyvox)?

Blocks formation of the initiation complex of the 50S and 30S subunits

12

What is the spectrum of activity of Linezolid (Zyvox)?

Predominantly Gram (+): S. aureus (MSSA, MRSA), S. epidermidis (MSSE, MRSE), E. faecalis (includes vanco-R strains), E. faecium (includes vanco-R strains), S. pneumoniae (includes Pen-I, Pen-R strains), S. pyogenes. Others: Corynebacterium, Listeria mnocytogenes, M. catarrhalis, H. influenzae, Legionella, C. difficile, C. perfringens, Bacteroides

13

What is the dosage/administration of Linezolid (Zyvox)?

Available as 600mg tablets, oral suspension, pre-made IVPB solution. Usual dosing - Adults: 600mg PO/IV Q12h. No adjustment needed in renal/hepatic failure

14

What is the PK of Linezolid (Zyvox)?

F ~100%. T1/2: 4.2-5.4 hrs. Distributes well to perfused tissue sites (pleural, pancreas)

15

What is the PD of Linezolid (Zyvox)?

Bacteriostatic against most ("cidal" against some Pneumococci). Concentration-independent killing. Resistance: 23S ribosomal RNA mutations. Minimal-moderate PAE. Best predictor of activity: Time > MIC

16

What are the ADRs associated with Linezolid (Zyvox)?

Nausea, diarrhea. Hematologic** (thrombocytopenia, anemia. Risk increases w/ duration of Rx (2 weeks or longer). Use of B6 may decrease risk of developing hematologic toxicity. Weekly CBC monitoring while on therapy). Liver (increased LFTs). CNS (peripheral neuropathy, optic neuritis (irreversible)). Rash. Lactic acidosis

17

What is a common DDI with Linezolid (Zyvox)?

SSRI's + MAOI (e.g. linezolid) --> Serotonin Syndrome

18

What are the clinical applications of Linezolid (Zyvox)?

Vanco-R enterococcal infections. MRSA infections (alternative to vanco)

19

What are some patient instructions for Linezolid (Zyvox)?

May take without regard to meals. Complete the full course of therapy. Inform MD/PharmD if any OTC meds including vitamins and herbal products, cough and cold preps. Inform MD/PharmD if taking any antidepressants. Inform MD if black, tarry stools, unusual bleeding. Pregnancy Category C

20

What should be avoided while on Linezolid (Zyvox)?

Aged cheese, aged meats, soy sauce, beer, red wine, sauerkraut

21

What is the MOA of Daptomycin?

Binds to the bacterial cell membrane (calcium-dependent insertion of lipid tail). Rapidly depolarizes the cell membrane (efflux of potassium, destroys ion-concentration gradient). Cell death (multiple failures in biosystems, DNA, RNA, and protein synthesis)

22

What is the spectrum of activity of Daptomycin?

Active against most isolates of the following both in vitro and in clinical infections. Aerobic and facultative Gram (+): Enterococcus faecalis (vanco-susceptible strains only). Staphylococcus aureus (including MRSA). Streptococcus agalactiae. Streptococcus dysgalactiae subsp. equisimilis. Streptococcus pyogenes

23

What is the PK of Daptomycin?

F not applicable (IV only). T1/2: 8-9 hrs. High protein binding (90%), slow distribution from plasma, small Vd, all suggest limited tissue penetration for deep-seated infection. No hepatic metabolism, > 80% renal elimination

24

What is the dosing/administration of Daptomycin like?

Daptomycin 4-6mg/kg should be administered over 30 minutes by intravenous infusion in 0.9% NaCl injectoin once every 24 hours. Dosing more frequently than QD is not recommended

25

What are the dosage modifications for Daptomycin like?

Elimination is primarily by the kidney. Dosage modification for patients with CrCl < 30, including patients receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD)

26

What is the PD of Daptomycin?

Concentration-dependent killing. Bactericidal. PAE: 6hrs. Resistance: clinical failures in MRSA bacteremia noted; mechanism not well defined

27

What is the key parameter for efficacy of Daptomycin?

Peak/MIC, AUC/MIC

28

What are the ADRs like for Daptomycin?

GI (constipation/N/D). CNS (HA, insomnia, dizziness). CPK elevations. Dermatologic (rash, itching). Eosinophilic pneumonia

29

What is Skeletal Myopathy with Daptomycin?

Patients receiving Daptomycin should be monitored for the development of muscle pain or weakness, particularly of the distal extremities (CPK levels monitored weekly). Patients who develop unexplained elevations in CPK while receiving Daptomycin should be monitored more frequently

30

What is Daptomycin's place in therapy?

FDA approved ONLY for the treatment of complicated skin and skin structure infections caused by susceptible organisms (e.g. MRSA) and bloodstream infections caused by S. aureus. Other indications include osteomyelitis

31

Review of therapy, what is Linezolids place in therapy?

MRSA - alternative to vanco if intolerance, clinical failures (vanco heteroresistance). VRE

32

Review of therapy, what is Quinupristin-Dalfopristins place in therapy?

MRSA - alternative to vanco if clinical failure or intolerance to linezolid. Synergy with vanco; combination therapy for recalcitrant infections

33

Review of therapy, what is Daptomycin's place in therapy?

For MRSA, alternative after vanco, linezolid. NOT indicated for pneumonia